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SummaryChronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.

Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.

Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.

Background: The oral ingestion of elemental mercury is unlikely to cause systemic toxicity, as it is poorly absorbed through the gastrointestinal system. However, abnormal gastrointestinal function or anatomy may allow elemental mercury into the bloodstream and the peritoneal space. Systemic effects of massive oral intake of mercury have rarely been reported. Case Report: In this paper, we are presenting the highest ingle oral intake of elemental mercury by a child aged 3 years. A Libyan boy aged 3 years ingested approximately 750 grams of elemental mercury and was still asymptomatic. Conclusion: The patient had no existing disease or abnormal gastrointestinal function or anatomy. The physical examination was normal. His serum mercury level was 91 μg/L (normal

Background We aimed to show the relationship between recurrence of wheezing and serum levels of vitamin D, zinc, and copper in wheezy children compared with a healthy group. Methods In this cross sectional study, seventy-three children with wheezing and seventy-five controls were included without a follow-up period. The clinical characteristics of the children were assessed, the asthma predictive index and temporal pattern of wheeze were determined. The serum levels of vitamin D, zinc, and copper were measured. Pearson correlation analysis was used to evaluate the relationship between homogeneously distributed variables. Results Thirty-two of the seventy-three children (43.8%) had more than three wheezing attacks (recurrent wheezing). The Asthma Predictive Index index was positive in 26 patients (35.6%). When classified to temporal pattern of wheeze, fifty-three of the study group (72.6%) had episodic wheezing and the remainder (27.4%) was classified as multiple-trigger wheezing. We found no overall significant difference between the study and control group in terms of vitamin D and trace elements . The vitamin D and zinc levels were significantly lower and serum copper and copper/zinc ratio was significantly higher in patients with recurrent wheezing (p =0.03, p

e12060 Background: Phyllodes tumor of the breast is a rare fibroepithelial lesion. Appropriate surgical and oncological management remains a subject of debate. The aim of this study was to determin...

Introduction: Behcet's disease (BD) is a multi-systemic disorder with muco-cutaneous, ocular, arthritic, vascular or central nervous system involvement. The role of gamma delta T cells is implicated in BD. The activation status of gamma delta T cells and their cytokine secretion against phosphoantigens are evaluated in BD. Methods: NKG2A, NKG2C, NKG2D, CD16 and CCR7 molecules on gamma delta T cells were analyzed in 70 BD, 27 tuberculosis (TB) patients and 26 healthy controls (HC). Peripheral gamma delta T cells were expanded with a phosphoantigen (BrHPP) and IL-2, restimulated with BrHPP and a TLR3 ligand, and cytokine production was measured. Results: gamma delta T cells were not increased in both BD and TB patients, but the proportions of TCRV delta 2(+) T cells were lower (58.9 and 50.7 vs. 71.7%, P = 0.04 and P = 0.005) compared to HC. Higher proportion of TCRV delta 2(+) T cells were CD16(+) (26.2 and 33.9 vs. 16.6%, P = 0.02 and P = 0.001) and CCR7(-) (32.2 and 27.9 vs. 17.7%, P < 0.0001 and P = 0.014) in BD and TB patients compared to HC. NKG2C(+) gamma delta(+) T cells were relatively increased (0.5 and 0.6 vs. 0.3%, P = 0.008 and 0.018), whereas NKG2D positivity was decreased in patients with BD and TB (77.7 and 75.8 vs. 87.5%, P = 0.001 and 0.004). Expansion capacity of gamma delta T cells in BD and TB as well as production of IL-13, IFN-gamma, granulocyte monocyte colony stimulating factor (GM-CSF), TNF-alpha, CCL4 and CCL5 in BD was lower compared to HC, when restimulated by TLR3 ligand and BrHPP. Conclusion: The changes on gamma delta T cells of BD as well as TB patients implicate that gamma delta T cells have already been exposed to regulatory effects, which changed their activity. Lower cytokine response of gamma delta T cells implicates down modulation of these cells in BD.